Cell Transformation, Neoplastic; Lung Neoplasms; Pathology; Receptor, Epidermal Growth Factor; Molecular Targeted Therapy
Mutations in the Epidermal Growth Factor Receptor (EGFR) are found in 10-20% of lung adenocarcinomas (a subtype of lung cancer). These mutations are most common in tumors in never-smokers and are associated with sensitivity to drugs that specifically block the activity of the mutant receptor. Patients with EGFR mutant tumors initially respond to treatment with these drugs, however drug-resistant disease almost invariably emerges within a year of starting treatment. In our laboratory we use genetically engineered mouse models of EGFR mutant lung cancer to study: 1) how the mutant receptors alter signaling pathways in lung cells to cause cancer and, 2) mechanisms of resistance to therapies directed against mutant EGFR.
Specialized Terms: Cancer biology; Mouse models of lung cancer; Epidermal Growth Factor Receptor; ERBB Receptor family; Targeted therapy
Erlotinib Resistance in Mouse Models of EGFR-Induced Lung Adenocarcinoma Resembles Drug Resistance in the Human Disease.
Politi K, Fan PD, Shen R, Zakowski M and Varmus H. Erlotinib Resistance in Mouse Models of EGFR-Induced Lung Adenocarcinoma Resembles Drug Resistance in the Human Disease. Dis Model Mech. 2010 Jan-Feb;3(1-2):111-9. Epub 2009 Dec 9. PMCID: 2806903
Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer.
Regales L, Gong Y, Shen R, De Stanchina E, Vivanco I, Goel A, Koutcher J, Spassova M, Oerfelli O, Mellingohoff I, Zakowski M, Politi K and Pao W. Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer.J Clin Invest. 2009 Oct;119(10):3000-10. doi: 10.1172/JCI38746. Epub 2009 Sep 14.PMCID: PMC2752070
Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors.
Regales L, Balak MN, Gong Y, Politi K, Sawai A, Le C, Koutcher JA, Solit DB, Rosen N, Zakowski MF, Pao W. Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors. PLoS ONE. 2007 Aug 29;2(8):e810.PMCID: 1950079
Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors.
Politi K, Zakowski MF, Fan PD, Schonfeld EA, Pao W, Varmus HE. Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors. Genes Dev. 2006 Jun 1;20(11):1496-510.
Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain.
Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG, Varmus H. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005 Mar;2(3):e73 Epub 2005 Feb 22.
EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib.
Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kris M, Varmus H. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13306-11. Epub 2004 Aug 25.PMCID: 516528
Full List of PubMed Publications
- Gettinger S, Choi J, Hastings K, Truini A, Datar I, Sowell R, Wurtz A, Dong W, Cai G, Melnick MA, Du VY, Schlessinger J, Goldberg SB, Chiang A, Sanmamed MF, Melero I, Agorreta J, Montuenga LM, Lifton R, Ferrone S, Kavathas P, Rimm DL, Kaech SM, Schalper K, Herbst RS, Politi K: Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer. Cancer Discov. 2017 Oct 12; 2017 Oct 12. PMID: 29025772
- Suda K, Rozeboom L, Rivard CJ, Yu H, Ellison K, Melnick MAC, Hinz TK, Chan D, Heasley LE, Politi K, Mitsudomi T, Hirsch FR: Therapy-induced E-cadherin downregulation alters expression of programmed death ligand-1 in lung cancer cells. Lung Cancer. 2017 Jul; 2017 Apr 19. PMID: 28577937
- Suda K, Rozeboom L, Furugaki K, Yu H, Melnick MAC, Ellison K, Rivard CJ, Politi K, Mitsudomi T, Hirsch FR: Increased EGFR Phosphorylation Correlates with Higher Programmed Death Ligand-1 Expression: Analysis of TKI-Resistant Lung Cancer Cell Lines. Biomed Res Int. 2017; 2017 Oct 8. PMID: 29119113
- McFadden DG, Politi K, Bhutkar A, Chen FK, Song X, Pirun M, Santiago PM, Kim-Kiselak C, Platt JT, Lee E, Hodges E, Rosebrock AP, Bronson RT, Socci ND, Hannon GJ, Jacks T, Varmus H: Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma. Proc Natl Acad Sci U S A. 2016 Oct 18; 2016 Oct 4. PMID: 27702896
- Gettinger S, Politi K: PD-1 Axis Inhibitors in EGFR- and ALK-Driven Lung Cancer: Lost Cause? Clin Cancer Res. 2016 Sep 15; 2016 Jul 28. PMID: 27470969
- Forloni M, Gupta R, Nagarajan A, Sun LS, Dong Y, Pirazzoli V, Toki M, Wurtz A, Melnick MA, Kobayashi S, Homer RJ, Rimm DL, Gettinger SJ, Politi K, Dogra SK, Wajapeyee N: Oncogenic EGFR Represses the TET1 DNA Demethylase to Induce Silencing of Tumor Suppressors in Cancer Cells. Cell Rep. 2016 Jul 12; 2016 Jun 23. PMID: 27346347
- Pirazzoli V, Ayeni D, Meador CB, Sanganahalli BG, Hyder F, de Stanchina E, Goldberg SB, Pao W, Politi K: Afatinib plus Cetuximab Delays Resistance Compared to Single-Agent Erlotinib or Afatinib in Mouse Models of TKI-Naïve EGFR L858R-Induced Lung Adenocarcinoma. Clin Cancer Res. 2016 Jan 15; 2015 Sep 4. PMID: 26341921
- Ayeni D, Politi K, Goldberg SB: Emerging Agents and New Mutations in EGFR-Mutant Lung Cancer. Clin Cancer Res. 2015 Sep 1; 2015 Jul 13. PMID: 26169963
- Politi K, Ayeni D, Lynch T: The Next Wave of EGFR Tyrosine Kinase Inhibitors Enter the Clinic. Cancer Cell. 2015 Jun 8. PMID: 26058074
- Politi K, Herbst RS: Lung cancer in the era of precision medicine. Clin Cancer Res. 2015 May 15. PMID: 25979927
- Morgensztern D, Politi K, Herbst RS: EGFR Mutations in Non-Small-Cell Lung Cancer: Find, Divide, and Conquer. JAMA Oncol. 2015 May. PMID: 26181013
- Bantikassegn A, Song X, Politi K: Isolation of epithelial, endothelial, and immune cells from lungs of transgenic mice with oncogene-induced lung adenocarcinomas. Am J Respir Cell Mol Biol. 2015 Apr. PMID: 25347711
- Song X, Fan PD, Bantikassegn A, Guha U, Threadgill DW, Varmus H, Politi K: ERBB3-independent activation of the PI3K pathway in EGFR-mutant lung adenocarcinomas. Cancer Res. 2015 Mar 15; 2015 Jan 16. PMID: 25596284
- Meador CB, Jin H, de Stanchina E, Nebhan CA, Pirazzoli V, Wang L, Lu P, Vuong H, Hutchinson KE, Jia P, Chen X, Eisenberg R, Ladanyi M, Politi K, Zhao Z, Lovly CM, Cross DA, Pao W: Optimizing the sequence of anti-EGFR-targeted therapy in EGFR-mutant lung cancer. Mol Cancer Ther. 2015 Feb; 2014 Dec 4. PMID: 25477325
- Politi K, Gettinger S: Perfect ALKemy: optimizing the use of ALK-directed therapies in lung cancer. Clin Cancer Res. 2014 Nov 15; 2014 Sep 16. PMID: 25228532
- Pirazzoli V, Nebhan C, Song X, Wurtz A, Walther Z, Cai G, Zhao Z, Jia P, de Stanchina E, Shapiro EM, Gale M, Yin R, Horn L, Carbone DP, Stephens PJ, Miller V, Gettinger S, Pao W, Politi K: Acquired resistance of EGFR-mutant lung adenocarcinomas to afatinib plus cetuximab is associated with activation of mTORC1. Cell Rep. 2014 May 22; 2014 May 9. PMID: 24813888
- de Bruin EC, Cowell C, Warne PH, Jiang M, Saunders RE, Melnick MA, Gettinger S, Walther Z, Wurtz A, Heynen GJ, Heideman DA, Gómez-Román J, García-Castaño A, Gong Y, Ladanyi M, Varmus H, Bernards R, Smit EF, Politi K, Downward J: Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer. Cancer Discov. 2014 May; 2014 Feb 17. PMID: 24535670
- Lockwood W, Politi K: MYCxing it up with FGFR1 in squamous cell lung cancer. Cancer Discov. 2014 Feb. PMID: 24501305
- Pirazzoli V, Politi K: Generation of drug-resistant tumors using intermittent dosing of tyrosine kinase inhibitors in mouse. Cold Spring Harb Protoc. 2014 Feb 1; 2014 Feb 1. PMID: 24492774
- Chacón KM, Petti LM, Scheideman EH, Pirazzoli V, Politi K, DiMaio D: De novo selection of oncogenes. Proc Natl Acad Sci U S A. 2014 Jan 7; 2013 Dec 16. PMID: 24344264
- Politi K, Lynch TJ: Two sides of the same coin: EGFR exon 19 deletions and insertions in lung cancer. Clin Cancer Res. 2012 Mar 15; 2012 Feb 8. PMID: 22317760
- Politi K, Pao W: How genetically engineered mouse tumor models provide insights into human cancers. J Clin Oncol. 2011 Jun 1; 2011 Jan 24. PMID: 21263096